title: S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab.
abstract: Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749-62. ©2013 AACR.
authors.affiliation: Corresponding Author: Mike F. Burbridge, Oncology Research and Development Unit, Institut de Recherches Servier, 125 chemin de Ronde, 78290 Croissy-sur-Seine, France. mike.burbridge@fr.netgrs.com.
authors.forename: Mike F
authors.initials: MF
authors.lastname: Burbridge
authors.forename: Céline J
authors.initials: CJ
authors.lastname: Bossard
authors.forename: Carine
authors.initials: C
authors.lastname: Saunier
authors.forename: Imre
authors.initials: I
authors.lastname: Fejes
authors.forename: Alain
authors.initials: A
authors.lastname: Bruno
authors.forename: Stéphane
authors.initials: S
authors.lastname: Léonce
authors.forename: Gilles
authors.initials: G
authors.lastname: Ferry
authors.forename: Georges
authors.initials: G
authors.lastname: Da Violante
authors.forename: François
authors.initials: F
authors.lastname: Bouzom
authors.forename: Valérie
authors.initials: V
authors.lastname: Cattan
authors.forename: Anne
authors.initials: A
authors.lastname: Jacquet-Bescond
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Brian P
authors.initials: BP
authors.lastname: Lockhart
authors.forename: Jean A
authors.initials: JA
authors.lastname: Boutin
authors.forename: Alex
authors.initials: A
authors.lastname: Cordi
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Ortuno
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
authors.forename: John A
authors.initials: JA
authors.lastname: Hickman
authors.forename: Francisco H
authors.initials: FH
authors.lastname: Cruzalegui
authors.forename: Stéphane
authors.initials: S
authors.lastname: Depil
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: C587436:3-((3-((4-(4-morpholinylmethyl)-1H-pyrrol-2-yl)methylene)-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl)-1,3-thiazolidine-2,4-dione; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D045162:Thiazolidinediones; D000068258:Bevacizumab; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase